mTORC1 and mTORC2 differentially regulate the development of NK cells

Abstract Natural killer (NK) cells are innate lymphoid cells that play essential roles in both innate and adaptive immunity. Kinase mTOR is critical for NK cell development; however, the unique roles of mTORC1 or mTORC2 in regulating this process remain unknown. Ncr1iCre-mediated conditional deletion of Rptor or Rictor (genes encoding defining component of mTORC1 or mTORC2, respectively) results in altered homeostatic NK cellularity and impaired development at distinct maturation stages. The transition from CD27+CD11b− to CD27+CD11b+ stage is impaired in Rptor cKO mice, while, the terminal maturation from CD27+CD11b+ to CD27−CD11b+ stage is compromised in Rictor cKO mice. Mechanistically, Raptor deficiency renders large alteration of the gene expression profile including transcription factors governing early NK cell development. Comparatively, loss of Rictor causes a restricted transcriptome changes. The reduced expression of T-bet correlates with the terminal maturation defects and results from impaired mTORC2-AktS473-FoxO1 signaling. To further explore the development of murine NK cells and the effects of Raptor or Rictor deficiency, single cell RNA sequencing analyses were performed. The Lin−NK1.1+ cells from BM of adult WT mice are unbiasedly classified into six different populations including CD3+ cells, ILC1, immature NK cells, two intermediate mature NK cells, and terminal mature NK cells. Most Raptor-deficient NK cells form new cluster that is not seen in either WT or Rictor cKO mice. Rictor deficiency affects the terminal maturation of NK cells and potentially the development of ILC1. Collectively, our results reveal the divergent roles of mTORC1 and mTORC2 in NK cell development.